Studies on Two Siblings with Recessive Dystrophic Epidermolysis bullosa (Hallopeau-Siemens) and the Piasminogen Activator and Its Inhibitor in the Lesion

Kaneko, Fumio; Tsukinaga, Ichiro; Ando, Masaaki; Ohkawara, Akira; Oguchi, Haruhisa; Oikawa, Kiyoshi; Nagai, Morihito

doi:10.1159/000248416

Cited by 4 publications

(2 citation statements)

References 9 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Increased activity of plasminogen activators, involved in the activation of MMPs, has been suggested to play a role in blister formation in RDEB patients [Kaneko et al, 1989]. The increased quantity of active MMP1 that we observed in the most affected patients could thus be due to a difference in the balance of activation/inhibition of plasmin by plasminogen activators (uPA, tPA) and by their inhibitors (PAIs).…”

Section: Discussionmentioning

confidence: 52%

A frequent functional SNP in theMMP1promoter is associated with higher disease severity in recessive dystrophic epidermolysis bullosa

Titeux¹,

Pendaries²,

Tonasso³

et al. 2008

Hum. Mutat.

View full text Add to dashboard Cite

Recessive dystrophic epidermolysis bullosa (RDEB) is caused by mutations in the COL7A1 gene encoding type VII collagen. Variations in severity between the different clinical forms of RDEB likely depend on the nature and location of COL7A1 mutations, but observed intrafamilial phenotypic variations suggest additional genetic and/or environmental factors. Candidate modifier genes include MMP1, encoding matrix metalloproteinase 1, the first gene implicated in RDEB before its primary role in the disease was excluded. Type VII collagen is a substrate of MMP1 and an imbalance between its synthesis and degradation could conceivably worsen the RDEB phenotype. Here, we studied a previously described family with three affected siblings of identical COL7A1 genotype but displaying great sibling-to-sibling variations in disease severity. RDEB severity did not correlate with type VII collagen synthesis levels, but with protein levels at the dermal-epidermal junction, suggesting increased degradation by metalloproteinases. This was supported by the presence of increased transcript and active MMP1 levels in the most severely affected children, who carried a known SNP (1G/2G) in the MMP1 promoter. This SNP creates a functional Ets binding site resulting in transcriptional upregulation. We next studied a French cohort of 31 unrelated RDEB patients harboring at least one in-frame COL7A1 mutation, ranging from mild localized RDEB to the severe Hallopeau-Siemens form. We found a strong genetic association between the 2G variant and the Hallopeau-Siemens disease type (odds ratio: 73.6). This is the first example of a modifier gene in RDEB and has implications for its prognosis and possible new treatments.

show abstract

Section: Discussionmentioning

confidence: 52%

A frequent functional SNP in theMMP1promoter is associated with higher disease severity in recessive dystrophic epidermolysis bullosa

Titeux¹,

Pendaries²,

Tonasso³

et al. 2008

Hum. Mutat.

View full text Add to dashboard Cite

show abstract

“…Their clinical phenotypes were as follows; three with dystrophic Hallopeau‐Siemens type (Patients 1–3), one with dystrophic non Hallopeau‐Siemens type (Patient 4), and the remaining one with non‐lethal junctional type without pyloric atresia (Patient 5). The details about Patients 2 and 4 have been reported previously (2, 7). Diagnoses were made on the basis of clinical, histological, and ultrastructural findings.…”

Section: To the Editormentioning

confidence: 99%

Increased Serum Levels of Interleukin-6, Immunoglobulin and Acute Phase Protein in Patients with the Severe Clinical Form of Inherited Epidermolysis Bullosa

Kawakami

Oyama

Ohtsuka

et al. 2005

The Journal of Dermatology

Self Cite

View full text Add to dashboard Cite

Exclusion of stromelysin-1, stromelysin-2, interstitial collagenase and fibronectin genes as the mutant loci in a family with recessive epidermolysis bullosa dystrophica and a form of cerebellar ataxia

et al. 1992

View full text Add to dashboard Cite

The interstitial collagenase gene (CLG), one of the main candidates in severe generalized recessive epidermolysis bullosa dystrophica (SGREBD), is closely linked to the stromelysin-1 (STMY1) and stromelysin-2 (STMY2) genes. These three loci map on chromosome 11 (q21-q22.3), where they constitute a cluster of genes coding for metalloproteinases involved in the degradation of the extracellular matrix (ECM). A recessive form of cerebellar ataxia of post-puberal onset (CLA1) has also been assigned to chromosome 11 (q14-q21). Since useful restriction fragment length polymorphisms (RFLPs) for the CLG gene are not available, we have studied the inheritance of the marker TaqI RFLP of the STMY1 gene in a North Italian family with a child affected by SGREBD, and his two sisters showing cerebellar ataxia (CA) of post-puberal onset. We have also studied the MspI RFLP of the fibronectin gene (FN1), which is located on chromosome 2q34-q36, and which codes for non-collagenous matrix proteins. Since we did not observe the segregation of the pathological phenotypes with STMY1 and FN1 RFLPs, we excluded the involvement of these genes in both the SGREBD and CA present in this family. The exclusion of the STMY1 gene indicates that the mutation causing SGREBD cannot be located in the CLG and/or STMY2 genes because of their proximity to the STMY1 locus. These data also indicate that the CA form here reported is not attributable to alterations in regions close to the collagenase cluster on chromosome 11.

show abstract

Studies on Two Siblings with Recessive Dystrophic Epidermolysis bullosa (Hallopeau-Siemens) and the Piasminogen Activator and Its Inhibitor in the Lesion

Cited by 4 publications

References 9 publications

A frequent functional SNP in theMMP1promoter is associated with higher disease severity in recessive dystrophic epidermolysis bullosa

A frequent functional SNP in theMMP1promoter is associated with higher disease severity in recessive dystrophic epidermolysis bullosa

Increased Serum Levels of Interleukin-6, Immunoglobulin and Acute Phase Protein in Patients with the Severe Clinical Form of Inherited Epidermolysis Bullosa

Exclusion of stromelysin-1, stromelysin-2, interstitial collagenase and fibronectin genes as the mutant loci in a family with recessive epidermolysis bullosa dystrophica and a form of cerebellar ataxia

Contact Info

Product

Resources

About